Fat for life: new stories on old grease

Abstract

DUE TO THE ALARMING EPIDEMIC in the modern world of obesity, dyslipidemia, and the parallel increasing prevalence of the related metabolic and cardiovascular diseases such as type 2 diabetes and atherosclerosis, the neutral lipids triglycerides and cholesteryl esters have a notorious reputation. The excessive accumulation of triglycerides reflects energy surplus, which ultimately causes the excessive adiposity that leads to obesity; in addition, the deposition of cholesteryl esters in the artery walls is an inevitable step for the fatty plaque formation hastening the development of atherosclerosis. Prevention and treatment of neutral lipid-related metabolic and cardiovascular diseases are major challenges for modern medicine. For many years, neutral lipids had been misperceived as “boring grease”. The primary reason is that these lipids are extremely hydrophobic. As a result, the biochemical studies regarding the synthesis and degradation of neutral lipids as well as the elucidation of their metabolic function were largely at the descriptive level. Enzymes involved in the metabolic flux of these lipids are often either intrinsic membrane proteins or favor an extremely hydrophobic environment, which has historically been difficult to isolate through traditional protein purification techniques. Fortunately, in the last two decades, powered with the revolution and the elegant combined use of methodologies in biochemistry, molecular biology, bioinformatics, cell biology, and forward and reverse genetics, we have witnessed an impressive transformation of the neutral lipid field. Today, many steps, if not all, of the neutral lipid metabolic pathways have been revealed in molecular detail. In addition, along with the improved analytic tools, the previously underappreciated complexity of neutral lipids has also started to be revealed. Cases have been identified that establish the relationship between specific species of neutral lipids and specific disease states. The purpose of this review series is to highlight such progress. Because of the richness of the science and the expansion of the field, nine excellent reviews have been divided into four separate parts, each of which will be published in this Journal over the next four consecutive issues. Part I: Pathways for De Novo Triglyceride Synthesis and Assimilation of Exogenous Dietary Fat In eukaryotes, triglycerides are synthesized through two major pathways, the glycerol phosphate pathway and the monoacylglycerol pathway. The glycerol phosphate pathway is believed to be present in the majority of cells and responsible for the de novo synthesis of triglycerides. In contrast, the monoacylglycerol pathway is known to play a major role in the small intestine for the absorption of exogenous dietary fat. The review by Drs. Takeuchi and Reue (7) details the complexity of the biochemistry and genetics of the glycerol phosphate pathway. The first committed step for this pathway is the acylation of glycerol-3-phosphate by glycerol phosphate acyltransferase (GPAT). A second fatty acid moiety is subsequently transferred to lysophosphatidic acid by acylglycerolphosphate acyltransferase (AGPAT) to produce phosphatidate, which in turn is converted to diacylglycerol through the action of phosphatidate phosphatase (PAP). PAP enzyme activity is conferred by the lipin protein family. Diacylglylcerol can either be further acylated by diacylglycerol acyltransferase (DGAT) to synthesize triglyceride or be used in phospholipid synthesis through the Kennedy pathway. In this review, the authors focus on three protein families: GPAT, AGPAT, and PAP enzymes. In the second review, Drs. Iqbal and Hussain (3) discuss the recent progress in the dietary fat absorption pathway. The major species of dietary fat is trigylceride. The remaining portion is comprised of a wide array of polar and nonpolar lipids, such as phospholipids, sterols, and many minor lipids including fat-soluble vitamins. The complicated process of dietary fat digestion and absorption can be divided into four sequential steps: the emulsification and hydrolysis of dietary fat in the lumen of the intestine, the uptake of hydrolyzed products by enterocytes, the resynthesis and packaging of fat into lipoproteins in the enterocytes, and last, the secretion of lipoproteins into circulation. In this context, the authors update the current knowledge pertaining to intestinal lipid absorption.